Progressive Neurodegeneration Research Articles

MRI deep learning demonstrates featured neuropathological deteriorations in the AD brain

AbstractBackgroundDeep learning (DL) of non‐invasive brain structural magnetic resonance imaging (sMRI) has shown superb performance in differentiating Alzheimer’s disease (AD) from cognitively healthy participants (HC). Attention is needed to tackle AD pathological progression on sMRI using interpretable DL methods. Here, we studied the feasibility of DL in identifying neurodegenerative progression patterns in AD.MethodData applied to the study were from the multi‐centre Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS) with 2,369 T1‐weighted brain images of 1,005 subjects. An interpretable DL technique named the ensemble 3‐dimensional convolutional neural network (Ensemble 3DCNN) was used to detect the longitudinal trajectory of sMRI changes during AD progression. The model used multiple 3D convolutional neural networks and a meta‐classifier to assess the degree of brain changes through generating an index score, named P‐score. The score was derived as the outcome of training and verifying the Ensemble 3DCNN model for difference in the whole‐brain sMRI between AD and HC. The predictive P‐scores values were used to analyze the sMRI images for mining neurodegenerative brain regions. In addition, dementia stages, and the temporal and spatial connectivity patterns of neurodegeneration progression were also analyzed.ResultBrain regions showing high P‐scores (> 0.73/1.00) included the amygdala, nucleus accumbens, agranular insular cortex, and the hippocampus, matching the isocortex, basal magnocellular complex, and transentorhinal regions identified in Braak staging. The P‐score increased over time in 82% of the degenerative brain regions. The impaired areas were often spatially connected, consistently across multiple time points in the progression of AD. The trajectory of regional brain changes displayed multiple patterns with complex individual variability.ConclusionThe interpretable 3D DL model demonstrated featured deteriorations on the AD sMRI images. The finding confirmed the neuropathological degeneration of AD and captured additional whole‐brain changes, especially, relating to the heterogeneity of AD expression.

Multiple patterns of structural brain change trajectories in AD: MRI deep learning verification with enhanced sequential pattern analysis

AbstractBackgroundOur recently proposed interpretable Ensemble 3DCNN deep learning (DL) technique has allowed the derivation of a P‐score based on brain structural magnetic resonance imaging (sMRI) modelling to predict patterned neurodegeneration in AD (https://doi.org/10.1002/advs.202204717). Sequential association rules with a support rate greater than 18% have been used to define a neurodegenerative progression pattern. To more prudently test the meaningfulness of the patterns found, we further calculated the lift values of the various sequential patterns underlying the suggested longitudinal sMRI changes.MethodThe lift value of an association rule is defined as the rule’s confidence rate divided by the support rate of the rule consequent, i.e., the support rate of the rule divided by the product of the support values of the rule consequent and the rule antecedent. For example, with {L.NAC}→{L.NAC, R.NAC} (https://doi.org/10.1002/advs.202204717), among the 167 AD subjects employed for analyzing neurodegenerative progression patterns, the number (N) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points examined was firstly calculated. Secondly, among the above‐mentioned 167 AD subjects, the number (M) of the subjects with at least an sMRI image containing only L.NAC as neurodegenerative regions at all time points examined was counted and the time point (P) corresponding to the selected (earlier/earliest) sMRI image was saved. Thirdly, among the above selected M subjects, the number (K) of the subjects with at least an sMRI image containing both L.NAC and R.NAC as neurodegenerative regions at all time points latter than the P was computed. Thus, lift value = (K/M)/(N/167).ResultThe lift values of the fifty sequential association rules reported in the recent paper (https://doi.org/10.1002/advs.202204717) ranged between 1.27 and 2.59(i.e., all > 1; Table 1), further confirming the longitudinal sMRI change patterns in AD.ConclusionThis study analyzing the lift values of the sequential association rules further verified the multiple patterns of longitudinal sMRI trajectories in AD brains, as reported recently. The research demonstrated featured and heterogeneous whole‐brain structural degeneration with AD progression.

The Effects of Transcranial Direct Current Stimulation in Patients with Mild Cognitive Impairment.

Transcranial direct current stimulation (tDCS) came into consideration in recent years as a promising, non-invasive form of neuromodulation for individuals suffering from mild cognitive impairment (MCI). MCI represents a transitional stage between normal cognitive aging and more severe cognitive decline, which appears in neurodegenerative diseases, such as Alzheimer's disease. Numerous studies have shown that tDCS can have several useful effects in patients with MCI. It is believed to enhance cognitive functions, including memory and attention, potentially slowing down the progression of neurodegeneration and cognitive decline. tDCS is believed to work by modulating neuronal activity and promoting synaptic plasticity in the brain regions associated with cognition. Moreover, tDCS is generally considered safe and well-tolerated, making it an attractive option for long-term therapeutic use in MCI. However, further research is needed to determine the optimal stimulation parameters and long-term effects of tDCS in this population, as well as its potential to serve as a complementary therapy alongside other interventions for MCI. In this review, we included 16 randomized clinical trials containing patients with MCI who were treated with tDCS. We aim to provide important evidence for the cognitive enhancement using tDCS in patients with MCI, summarizing the effects and conclusions found in several clinical trials, and discuss its main mechanisms.

Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress.

Cholesterol trafficking is initiated by the endocytic pathway and transported from endo/lysosomes to other intracellular organelles. Deficiencies in cholesterol-sensing and binding proteins NPC1 and NPC2 induce accumulation in lysosomes and the malfunction of trafficking to other organelles. Each organelle possesses regulatory factors to induce cholesterol trafficking. The mutation of NPC1 and NPC2 genes induces Niemann-Pick disease type C (NPDC), which is a hereditary disease and causes progressive neurodegeneration, developmental disability, hypotonia, and ataxia. Oxidative stress induces damage in NPDC-related intracellular organelles. Although studies on the relationship between NPDC and oxidation are relatively rare, several studies have reported the therapeutic potential of antioxidants in treating NPDC. Investigating antioxidant drugs to relieve oxidative stress and cholesterol accumulation is suggested to be a powerful tool for developing treatments for NPDC. Understanding NPDC provides challenging issues in understanding the oxidative stress-lysosome metabolism of the lipid axis. Thus, we elucidated the relationship between complexes of intracellular organelles and NPDC to develop our knowledge and suggested potential antioxidant reagents for NPDC therapy.

Lysoglycosphingolipids have the ability to induce cell death through direct PI3K inhibition.

Sphingolipidoses are inherited metabolic disorders associated with glycosphingolipids accumulation, neurodegeneration, and neuroinflammation leading to severe neurological symptoms. Lysoglycosphingolipids (lysoGSLs), also known to accumulate in the tissues of sphingolipidosis patients, exhibit cytotoxicity. LysoGSLs are the possible pathogenic cause, but the mechanisms are still unknown in detail. Here, we first show that lysoGSLs are potential inhibitors of phosphoinositide 3-kinase (PI3K) to reduce cell survival signaling. We found that phosphorylated Akt was commonly reduced in fibroblasts from patients with sphingolipidoses, including GM1/GM2 gangliosidoses and Gaucher's disease, suggesting the contribution of lysoGSLs to the pathogenesis. LysoGSLs causedcell death and decreased the level of phosphorylated Akt as in the patient fibroblasts. Extracellularly administered lysoGM1 permeated the cell membrane to diffusely distribute in the cytoplasm. LysoGM1 and lysoGM2 also inhibited the production of phosphatidylinositol-(3,4,5)-triphosphate and the translocation of Akt from the cytoplasm to the plasma membrane. We also predicted that lysoGSLs could directly bind to the catalytic domain of PI3K by in silico docking study, suggesting that lysoGSLs could inhibit PI3K by directly interacting with PI3K in the cytoplasm. Furthermore, we revealed that the increment of lysoGSLs amounts in the brain of sphingolipidosis model mice correlated with the neurodegenerative progression. Our findings suggest that the down-regulation of PI3K/Akt signaling by direct interaction of lysoGSLs with PI3K in the brains is a neurodegenerative mechanism in sphingolipidoses. Moreover, we could propose the intracellular PI3K activation or inhibition of lysoGSLs biosynthesis as novel therapeutic approaches for sphingolipidoses because lysoGSLs should be cell death mediators by directly inhibiting PI3K, especially in neurons.

Alzheimer's Targeted Treatments: Focus on Amyloid and Inflammation.

Alzheimer's disease (AD) is the major cause of dementia that is now threatening the lives of billions of elderly people on the globe, and recent progress in the elucidation of the pathomechanism of AD is now opening venue to tackle the disease by developing and implementing "disease-modifying therapies" that directly act on the pathophysiology and slow down the progression of neurodegeneration. A recent example is the success of clinical trials of anti-amyloid b antibody drugs, whereas other therapeutic targets, e.g., inflammation and tau, are being actively investigated. In this dual perspective session, we plan to have speakers from leading pharmas in the field representing distinct investments in the AD space, which will be followed by the comment from scientific leadership of the Alzheimer's Association who will speak on behalf of all stakeholders. Neuroscientists participating in the Society for Neuroscience may be able to gain insights into the cutting edge of the therapeutic approaches to AD and neurodegenerative disorders, and discuss future contribution of neuroscience to this field.

Gut-brain axis: gut dysbiosis and psychiatric disorders in Alzheimer’s and Parkinson’s disease

Gut dysbiosis and psychiatric symptoms are common early manifestations of Alzheimer’s disease (AD) and Parkinson’s disease (PD). These diseases, characterised by progressive neuron loss and pathological protein accumulation, impose debilitating effects on patients. Recently, these pathological proteins have been linked with gut dysbiosis and psychiatric disorders. The gut-brain axis links the enteric and central nervous systems, acting as a bidirectional communication pathway to influence brain function and behavior. The relationship triad between gut dysbiosis, psychiatric disorders, and neurodegeneration has been investigated in pairs; however, evidence suggests that they are all interrelated and a deeper understanding is required to unravel the nuances of neurodegenerative diseases. Therefore, this review aims to summarise the current literature on the roles of gut dysbiosis and psychiatric disorders in pathological protein-related neurodegenerative diseases. We discussed how changes in the gut environment can influence the development of psychiatric symptoms and the progression of neurodegeneration and how these features overlap in AD and PD. Moreover, research on the interplay between gut dysbiosis, psychiatric disorders, and neurodegeneration remains in its early phase. In this review, we highlighted potential therapeutic approaches aimed at mitigating gastrointestinal problems and psychiatric disorders to alter the rate of neurodegeneration. Further research to assess the molecular mechanisms underlying AD and PD pathogenesis remains crucial for developing more effective treatments and achieving earlier diagnoses. Moreover, exploring non-invasive, early preventive measures and interventions is a relatively unexplored but important avenue of research in neurodegenerative diseases.

Improvement effects of green tea and pumpkin oils on myelin oligodendrocyte glycoprotein-induced Multiple sclerosis in rats

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) associated with significant progressive neurodegeneration. There is a lot of interest in the use of plant-based essential oils in traditional medicine to treat and prevent human illnesses, including MS. This research aimed to assess the neuroprotective effects of green tea oil (GTO) and pumpkin oil (PO) against myelin oligodendrocyte glycoprotein (MOG)-induced MS in Wistar rats as well as investigate the underlying molecular mechanisms. The Wistar rats were divided into four groups: group 1, normal control; group 2, MOG-injected; and groups 3 and 4, MOG-injected groups treated with 5 ml/kg body weight each of GTO and PO, respectively. The chemical profiles of components within a GTO and PO were identified using gas chromatography-mass spectrometry (GC–MS). Treatment with GTO and PO substantially improved the decreased dopamine, serotonin, norepinephrine, and acetylcholine levels in the brain of the MOG-injected rats. It also suppressed the elevated epinephrine levels. The histological injuries in the brain cortical tissue of the MOG-injected group were notably improved after supplementing with GTO and PO. Furthermore, brain lipid peroxidation and serum INF-β concentration were significantly lower in the MOG-injected rats treated with GTO and PO. The brain GSH, SOD, GPx, as well as serum coenzyme Q10, and α-tocopherol levels were significantly enhanced by GTO and PO supplementaion. Additionally, GTO and PO administration into MOG-injected rats significantly upregulated Nrf2, Bcl-2, and PCNA while significantly downregulated TNF-α, NF-κB, iNOS, p53, and Bax expression levels. Taken together, these findings suggest that GTO and PO efficiently ameliorate MOG-induced MS via enhancing the antioxidant, anti-inflammatory, and anti-apoptotic effects.

Repeated sleep deprivation decreases the flux into hexosamine biosynthetic pathway/O-GlcNAc cycling and aggravates Alzheimer’s disease neuropathology in adult zebrafish

This study investigated chronic and repeated sleep deprivation (RSD)-induced neuronal changes in hexosamine biosynthetic pathway/O-linked N-acetylglucosamine (HBP/O-GlcNAc) cycling of glucose metabolism and further explored the role of altered O-GlcNAc cycling in promoting neurodegeneration using an adult zebrafish model. RSD-triggered degenerative changes in the brain led to impairment of memory, neuroinflammation and amyloid beta (Aβ) accumulation. Metabolite profiling of RSD zebrafish brain revealed a significant decrease in glucose, indicating a potential association between RSD-induced neurodegeneration and dysregulated glucose metabolism. While RSD had no impact on overall O-GlcNAcylation levels in the hippocampus region, changes were observed in two O-GlcNAcylation-regulating enzymes, specifically, a decrease in O-GlcNAc transferase (OGT) and an increase in O-GlcNAcase (OGA). Glucosamine (GlcN) treatment induced an increase in O-GlcNAcylation and recovery of the OGT level that was decreased in the RSD group. In addition, GlcN reversed cognitive impairment by RSD. GlcN reduced neuroinflammation and attenuated Aβ accumulation induced by RSD. Repeated treatment of zebrafish with diazo-5-oxo-l-norleucine (DON), an inhibitor of HBP metabolism, resulted in cognitive dysfunction, neuroinflammation and Aβ accumulation, similar to the effects of RSD. The pathological changes induced by DON were restored to normal upon treatment with GlcN. Both the SD and DON-treated groups exhibited a common decrease in glutamate and γ-aminobutyric acid compared to the control group. Overexpression of OGT in zebrafish brain rescued RSD-induced neuronal dysfunction and neurodegeneration. RSD induced a decrease in O-GlcNAcylation of amyloid precursor protein and increase in β-secretase activity, which were reversed by GlcN treatment. Based on the collective findings, we propose that dysregulation of HBP and O-GlcNAc cycling in brain plays a crucial role in RSD-mediated progression of neurodegeneration and Alzheimer’s disease pathogenesis. Targeting of this pathway may, therefore, offer an effective regulatory approach for treatment of sleep-associated neurodegenerative disorders.

Serum metabolomics identified specific lipid compounds which may serve as markers of disease progression in patients with Alström and Bardet-Biedl syndromes.

Objectives: Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are among the so-called ciliopathies and are associated with the development of multiple systemic abnormalities, including early childhood obesity and progressive neurodegeneration. Given the progressive deterioration of patients' quality of life, in the absence of defined causal treatment, it seems reasonable to identify the metabolic background of these diseases and search for their progression markers. The aim of this study was to find metabolites characteristic to ALMS and BBS, correlating with clinical course parameters, and related to the diseases progression. Methods: Untargeted metabolomics of serum samples obtained from ALMS and BBS patients (study group; n = 21) and obese/healthy participants (control group; each of 35 participants; n = 70) was performed using LC-QTOF-MS method at the study onset and after 4years of follow-up. Results: Significant differences in such metabolites as valine, acylcarnitines, sphingomyelins, phosphatidylethanolamines, phosphatidylcholines, as well as lysophosphatidylethanolamines and lysophosphatidylcholines were observed when the study group was compared to both control groups. After a follow-up of the study group, mainly changes in the levels of lysophospholipids and phospholipids (including oxidized phospholipids) were noted. In addition, in case of ALMS/BBS patients, correlations were observed between selected phospholipids and glucose metabolism parameters. We also found correlations of several LPEs with patients' age (p < 0.05), but the level of only one of them (hexacosanoic acid) correlated negatively with age in the ALMS/BBS group, but positively in the other groups. Conclusion: Patients with ALMS/BBS have altered lipid metabolism compared to controls or obese subjects. As the disease progresses, they show elevated levels of lipid oxidation products, which may suggest increased oxidative stress. Selected lipid metabolites may be considered as potential markers of progression of ALMS and BBS syndromes.

Frontline Venetoclax Therapy for 18-Year-Old Male with Ataxia Telangiectasia and Early T-Cell Precursor Acute Lymphoblastic Leukemia

Ataxia Telangiectasia (AT) is an autosomal recessive disorder which is associated with progressive neurodegeneration, immunodeficiency, and predisposition to cancer. Specifically, around 40% of patients with AT will develop malignancy during their lifetime, most commonly lymphoid malignancies. Patients with AT have increased toxicity to chemotherapy and radiation, which necessitates modified and individualized therapy approaches. Early T-cell precursor ALL (ETP-ALL) is considered high risk and venetoclax has emerged as potential therapy combined with other chemotherapy to help achieve remission but there have been no reports of venetoclax use in patients with AT. Here, we present a case of an 18-year-old male with Ataxia Telangiectasia diagnosed with ETP-ALL, who achieved remission after therapy was augmented with venetoclax during consolidation phase of chemotherapy. The patient initially presented with lower limb swelling, fatigue and nose bleeds and found to have a white cell count (WBC) of 107 K/uL with 72% peripheral blasts. He was treated with steroid monotherapy for 38 days prior to presentation to our institution. On arrival to our institution he had a WBC count of 42 K/uL with 75 % blasts in peripheral blood. His bone marrow evaluation had 83% blasts. Flow cytometry was positive for CD3, CD5 (partial), CD7, CD38, CD45, CD54, CD56, CD 117 (partial), negative for MPO, TdT, HLA-DR. This confirmed the diagnosis of ETP-ALL. An 81 gene panel testing was positive for NOTCH 1, SRSF2, EZH2, CREBBP. No abnormal fusions or translocations were present, and cytogenetics did not reveal a clonal abnormality. Induction chemotherapy was given as per COG AALL1231 protocol with dose modifications including 50% decrease in vincristine and cyclophosphamide. His end of induction (EOI) bone marrow evaluation was positive for 32% MRD. Molecular diagnosis positive for NOTCH1, SRSF2 and EZH2. As it is not uncommon for patients with ETP-ALL to have persistent disease after induction chemotherapy cycle, we proceeded with consolidation per AALL0434 protocol with Nelarabine. Unfortunately, even with dose reduced vincristine he developed vocal cord paralysis, lower extremity neuropathy and urinary retention, hence vincristine was omitted. Bone marrow evaluation was repeated mid consolidation and was still positive for 20% MRD. Due to significant modifications in therapy as well as persistent disease midway through consolidation, venetoclax was added to augment therapy during the consolidation phase. He was given 150 mg/m2 for 7 days directly followed by nelarabine. End of consolidation marrow was negative for MRD, and molecular testing (81 gene panel) was also negative. He tolerated venetoclax well without any significant toxicities and remains in remission 4 months post therapy with venetoclax. This report indicates that venetoclax can be used safely in patients with AT. This patient showed persistent MRD positive mid-way through consolidation with negativity after augmentation with venetoclax. Patients with AT have increased risk of toxicity from chemotherapy agents which requires dose modifications in their chemotherapy regimen. Venetoclax augmentation may be a viable approach for patients with AT or DNA repair disorders.

Tagged IDS causes efficient and engraftment-independent prevention of brain pathology during lentiviral gene therapy for Mucopolysaccharidosis type II

Mucopolysaccharidosis type II (OMIM 309900) is a lysosomal storage disorder caused by iduronate 2-sulfatase (IDS) deficiency and accumulation of glycosaminoglycans, leading to progressive neurodegeneration. As intravenously infused enzyme replacement therapy cannot cross the blood-brain barrier (BBB), it fails to treat brain pathology, highlighting the unmet medical need to develop alternative therapies. Here, we test modified versions of hematopoietic stem and progenitor cell (HSPC)-mediated lentiviral gene therapy (LVGT) using IDS tagging in combination with the ubiquitous MND promoter to optimize efficacy in brain and to investigate its mechanism of action. We find that IDS tagging with IGF2 or ApoE2, but not RAP12x2, improves correction of brain heparan sulfate and neuroinflammation at clinically relevant vector copy numbers. HSPC-derived cells engrafted in brain show efficiencies highest in perivascular areas, lower in choroid plexus and meninges, and lowest in parenchyma. Importantly, the efficacy of correction was independent of the number of brain-engrafted cells. These results indicate that tagged versions of IDS can outperform untagged IDS in HSPC-LVGT for the correction of brain pathology in MPS II, and they imply both cell-mediated and tag-mediated correction mechanisms, including passage across the BBB and increased uptake, highlighting their potential for clinical translation.

Pharmacological Inhibition of the AQP4 Water Channel Activity Causes an Aggravation of Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s Disease

The misfolding of the protein α-synuclein, which leads to the formation of neurototoxic oligomers and aggregates, is one of the main causes of loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) in Parkinson’s disease (PD). We previously found that pharmacological inhibition of the water channel aquaporin-4 (AQP4), participating in the mechanisms of brain clearance of amyloidogenic proteins, caused the aggravation of neurodegeneration in the nigrostriatal system and the development of motor disturbances in a lactacystin model of PD. It was hypothesized that the progression of neurodegeneration can be a result of the excessive accumulation of pathologic forms of α-synuclein due to the AQP4 inhibition. The aim of this study is to determine whether pharmacological inhibition of AQP4 activity in a rat model of preclinical PD leads to an aggravation in α-synuclein pathology. The experiments were performed on male Wistar rats. AQP4 activity was suppressed using the intracerebroventricular injection of inhibitor TGN-020. To reproduce the model of the preclinical stage of PD, a specific proteasome inhibitor lactacystin (LC) was used. It was injected bilaterally into the SNpc. Immunoblotting methods and confocal microscopy were applied. The LC model of PD was characterized by a pathologic accumulation of total water-soluble and Ser129-phosphorylated forms of α-synuclein, as well as by formation of insoluble α-synuclein aggregates in the DA-neurons of SNpc. TGN-020 caused a significant aggravation of α-synuclein pathology in the LC model of PD. It was manifested by a marked increase in the level of water-soluble and modified forms of α-synuclein and by the 1.9-fold rise in the amount of α-synuclein aggregates in SN. We suppose that the disfunction of AQP4 which is involved in glymphatic system functioning, can be one of the mechanisms leading to the neurodegeneration and accumulation of amyloidogenic proteins in brain parenchyma during PD. The water channel AQP4 might be a target for the development of new therapeutic approaches aimed at attenuation of the cytotoxicity, accumulation and distribution of α-synuclein during the development of PD-like pathology.

Research Progress of α-Synuclein Aggregation Inhibitors for Potential Parkinson's Disease Treatment.

Parkinson's disease (PD) is characterized by fibrillation of disordered proteins known as Lewy bodies in the substantia nigra that also undergo progressive neurodegeneration. The aggregation of α-synuclein (α-syn) is a hallmark and potentially a critical step in the development of Parkinson's disease and other synucleinopathies. The synaptic vesicle protein α-syn is a small, abundant, highly conserved disordered protein and the causative agent of neurodegenerative diseases. Several novel pharmacologically active compounds are used to treat PD and other neurodegenerative disorders. Though, the mechanism through which these molecules inhibit the α-syn aggregation is still not fully understood. This review article is focused on the recent advancements in compounds that can inhibit the development of α-syn fibrillation and oligomerization. The current review article is based on the most recent and frequently cited papers from Google Scholar, SciFinder, and Researchgate sources. In the progression of PD, the mechanism of α-syn aggregation involves the structural transformation from monomers into amyloid fibrils. As the accumulation of α-syn in the brain has been linked to many disorders, the recent search for disease-modifying medications mainly focused on modifying the α-syn aggregation. This review contains a detailed report of literature findings and illustrates the unique structural features, structure-activity relationship, and therapeutic potential of the natural flavonoids in the inhibition of α-syn are also discussed. Recently, many naturally occurring molecules such as curcumin, polyphenols, nicotine, EGCG, and stilbene have been recognized to inhibit the fibrillation and toxicity of α-syn. Therefore, knowing the α-synuclein filament's structure and how they originate will help invent particular biomarkers for synucleinopathies and develop reliable and effective mechanism-based therapeutics. We hope the information this review provides may help evaluate novel chemical compounds, such as α-syn aggregation inhibitors, and will contribute to developing novel drugs for treating Parkinson's disease.

Receptor-based approaches and therapeutic targets in Alzheimer’s disease along with role of AI in drug designing: Unraveling pathologies and advancing treatment strategies

Alzheimer’s disease (AD) is a prevalent cause of dementia in the elderly, characterized by progressive cognitive decline and neurodegeneration. This review focuses on the etiology of AD, the role of various receptors [TNF (Tumor necrosis factor) receptor, nAChR (Neuronal nicotinic acetylcholine receptors), NMDARs (N-Methyl-D-aspartate receptors), APOE (Apolipoprotein E) receptor, and amyloid-beta receptor], and risk factors contributing to its development. AD progresses through mild, moderate, and severe stages, each exhibiting distinct symptoms. The hallmark pathologies are neurofibrillary tangles and amyloid plaques, comprised of hyperphosphorylated tau protein and amyloid-beta peptides, respectively. Current pharmacotherapeutic options alleviate symptoms but lack a complete cure. To address the challenges in developing effective AD treatments, researchers have turned to artificial intelligence (AI) and computational approaches in drug design. AI techniques, including machine learning and molecular docking, enable the analysis of large datasets and prediction of molecular interactions between potential drug candidates and target receptors. Virtual screening and molecular modeling aid in identifying novel therapeutic compounds. Predictive modeling and optimization algorithms optimize drug properties and predict efficacy. AI also facilitates the repurposing of existing drugs by analyzing their interactions with AD-related receptors and pathways. Clinical trial optimization using AI algorithms enhances patient selection, treatment monitoring, and outcome prediction. Integrating AI into AD drug design holds tremendous promise for accelerating the discovery of effective interventions. By leveraging AI’s capabilities, researchers can efficiently analyze extensive data, predict drug-target interactions, and optimize drug properties, leading to the identification of novel AD treatments. However, further research and validation are needed to translate AI-driven drug design approaches into clinically viable solutions for AD patients. Through continued advancements in AI and collaborative efforts, the development of targeted and advanced therapies for AD is within reach.

Global Proteomics for Identifying the Alteration Pathway of Niemann–Pick Disease Type C Using Hepatic Cell Models

Niemann–Pick disease type C (NPC) is an autosomal recessive disorder with progressive neurodegeneration. Although the causative genes were previously identified, NPC has unclear pathophysiological aspects, and patients with NPC present various symptoms and onset ages. However, various novel biomarkers and metabolic alterations have been investigated; at present, few comprehensive proteomic alterations have been reported in relation to NPC. In this study, we aimed to elucidate proteomic alterations in NPC and perform a global proteomics analysis for NPC model cells. First, we developed two NPC cell models by knocking out NPC1 using CRISPR/Cas9 (KO1 and KO2). Second, we performed a label-free (LF) global proteomics analysis. Using the LF approach, more than 300 proteins, defined as differentially expressed proteins (DEPs), changed in the KO1 and/or KO2 cells, while the two models shared 35 DEPs. As a bioinformatics analysis, the construction of a protein–protein interaction (PPI) network and an enrichment analysis showed that common characteristic pathways such as ferroptosis and mitophagy were identified in the two model cells. There are few reports of the involvement of NPC in ferroptosis, and this study presents ferroptosis as an altered pathway in NPC. On the other hand, many other pathways and DEPs were previously suggested to be associated with NPC, supporting the link between the proteome analyzed here and NPC. Therapeutic research based on these results is expected in the future.

Dopaminergic neurodegeneration in the substantia nigra is associated with olfactory dysfunction in mice models of Parkinson’s disease

Olfactory dysfunction represents a prodromal stage in Parkinson’s disease (PD). However, the mechanisms underlying hyposmia are not specified yet. In this study, we first observed an early olfactory dysfunction in mice with intragastric rotenone administration, consistent with dopaminergic neurons loss and α-synuclein pathology in the olfactory bulb. However, a much severer olfactory dysfunction was observed without severer pathology in olfactory bulb when the loss of dopaminergic neurons in the substantia nigra occurred. Then, we established the mice models by intrastriatal α-synuclein preformed fibrils injection and demonstrated the performance in the olfactory discrimination test was correlated to the loss of dopaminergic neurons in the substantia nigra, without any changes in the olfactory bulb analyzed by RNA-sequence. In mice with intranasal ferric ammonium citrate administration, we observed olfactory dysfunction when dopaminergic neurodegeneration in substantia nigra occurred and was restored when dopaminergic neurons were rescued. Finally we demonstrated that chemogenetic inhibition of dopaminergic neurons in the substantia nigra was sufficient to cause hyposmia and motor incoordination. Taken together, this study shows a direct relationship between nigral dopaminergic neurodegeneration and olfactory dysfunction in PD models and put forward the understandings that olfactory dysfunction represents the early stage of neurodegeneration in PD progression.

Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases.

Reelin is an extracellular matrix glycoprotein involved in neuronal migration during embryonic brain development and synaptic plasticity in the adult brain. The role of Reelin in the developing central nervous system has been extensively characterized. Indeed, a loss of Reelin or a disruption in its signaling cascade leads to neurodevelopmental defects and is associated with ataxia, intellectual disability, autism, and several psychiatric disorders. In the adult brain, Reelin is critically involved in neurogenesis and synaptic plasticity. Reelin's signaling potentiates glutamatergic and GABAergic neurotransmission, induces synaptic maturation, and increases AMPA and NMDA receptor subunits' expression and activity. As a result, there is a growing literature reporting that a loss of function and/or reduction of Reelin is implicated in numerous neurodegenerative diseases. The present review summarizes the current state of the literature regarding the implication of Reelin and Reelin-mediated signaling during aging and neurodegenerative disorders, highlighting Reelin as a possible target in the prevention or treatment of progressive neurodegeneration.

The NLRP3 Inflammasome in Neurodegenerative Disorders: Insights from Epileptic Models.

Neuroinflammation represents a dynamic process of defense and protection against the harmful action of infectious agents or other detrimental stimuli in the central nervous system (CNS). However, the uncontrolled regulation of this physiological process is strongly associated with serious dysfunctional neuronal issues linked to the progression of CNS disorders. Moreover, it has been widely demonstrated that neuroinflammation is linked to epilepsy, one of the most prevalent and serious brain disorders worldwide. Indeed, NLRP3, one of the most well-studied inflammasomes, is involved in the generation of epileptic seizures, events that characterize this pathological condition. In this context, several pieces of evidence have shown that the NLRP3 inflammasome plays a central role in the pathophysiology of mesial temporal lobe epilepsy (mTLE). Based on an extensive review of the literature on the role of NLRP3-dependent inflammation in epilepsy, in this review we discuss our current understanding of the connection between NLRP3 inflammasome activation and progressive neurodegeneration in epilepsy. The goal of the review is to cover as many of the various known epilepsy models as possible, providing a broad overview of the current literature. Lastly, we also propose some of the present therapeutic strategies targeting NLRP3, aiming to provide potential insights for future studies.

Neuroimaging of tissue microstructure as a marker of neurodegeneration in the AT(N) framework: defining abnormal neurodegeneration and improving prediction of clinical status

BackgroundAlzheimer’s disease involves accumulating amyloid (A) and tau (T) pathology, and progressive neurodegeneration (N), leading to the development of the AD clinical syndrome. While several markers of N have been proposed, efforts to define normal vs. abnormal neurodegeneration based on neuroimaging have been limited. Sensitive markers that may account for or predict cognitive dysfunction for individuals in early disease stages are critical.MethodsParticipants (n = 296) defined on A and T status and spanning the AD-clinical continuum underwent multi-shell diffusion-weighted magnetic resonance imaging to generate Neurite Orientation Dispersion and Density Imaging (NODDI) metrics, which were tested as markers of N. To better define N, we developed age- and sex-adjusted robust z-score values to quantify normal and AD-associated (abnormal) neurodegeneration in both cortical gray matter and subcortical white matter regions of interest. We used general logistic regression with receiver operating characteristic (ROC) and area under the curve (AUC) analysis to test whether NODDI metrics improved diagnostic accuracy compared to models that only relied on cerebrospinal fluid (CSF) A and T status (alone and in combination).ResultsUsing internal robust norms, we found that NODDI metrics correlate with worsening cognitive status and that NODDI captures early, AD neurodegenerative pathology in the gray matter of cognitively unimpaired, but A/T biomarker-positive, individuals. NODDI metrics utilized together with A and T status improved diagnostic prediction accuracy of AD clinical status, compared with models using CSF A and T status alone.ConclusionUsing a robust norms approach, we show that abnormal AD-related neurodegeneration can be detected among cognitively unimpaired individuals. Metrics derived from diffusion-weighted imaging are potential sensitive markers of N and could be considered for trial enrichment and as outcomes in clinical trials. However, given the small sample sizes, the exploratory nature of the work must be acknowledged.